Buprenorphine, chemically known as 21-cyclopropyl-7α-(2-hydroxy-3,3-dimethyl-2-b 1)-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine, is a semi-synthetic opiate used as a powerful analgesic and is indicated for the treatment of moderate to severe pain and opioid dependence. The compound was first reported by K. W. Bentley in U.S. Pat. No. 3,433,791. This patent reports the semi-synthesis of buprenorphine from thebaine as depicted in Scheme-1.

Various methods for the preparation of buprenorphine are reported in the prior art. The following documents disclose methods for preparing buprenorphine wherein thebaine is used as a key starting material.
US 2011/0152527A1 discloses a process for the preparation of buprenorphine as depicted in Scheme-2. The process up to Formula-V is similar to the Bentley process reported in U.S. Pat. No. 3,433,791. However, major modifications include the use of ethyl chloroformate and then heating at 130° C. to 140° C. with KOH and diethylene glycol for N-demethylation of the compound of Formula-V to get the compound of Formula-VII; the subsequent reaction with cyclopropyl methyl alcohol with mesyl chloride for N-alkylation; and finally the use of thiophenol for O-demethylation to get buprenorphine base of Formula-I. The overall reported yield of the process is only 27% of buprenorphine base from thebaine. In addition, the workup procedure for O-demethylation is tedious and there is no mention of the purity of the product and intermediates. Furthermore, the process uses hazardous, highly flammable and peroxide forming solvents, for example diethyl ether and THF, which makes the process unsuitable at an industrial scale. Finally, the process requires an extra step for purification, resulting in a low yield of the final product.

WO 2013/050748 of Johnson Matthey PTC discloses a process for the preparation of buprenorphine or its derivatives, as shown in Scheme-3 below. The preparation of the compound of Formula-VI is performed by known processes. However, major modifications include N-demethylation, which is carried out at lower temperatures using NaOH, water and ethylene glycol or methoxy ethanol and then subsequent O-demethylation using a different combination of thiols and bases to get the compound of Formula-XI. This compound is further converted to buprenorphine using methods known in the prior art. The publication does not disclose the formation of compound of Formula-VI and starts with this advance intermediate. The first reaction is N-demethylation, which is followed by 3-O-demethylation to get the compound of Formula-XI which is further converted to buprenorphine. A disadvantage associated with this process is the formation of impurities which arises during the final step of N-alkylation, as alkylation can occur on both the NH group and 3-phenolic group. Thus, additional steps for purification may be required, which lead to poor yield and lower quality of the final product. It is further mentioned that 3-O-demethylation cannot happen on the N-alkylcycloalkylated intermediate. For that reason, both N-demethylation and O-demethylation are carried out prior to the N-alkylation step.


One drawback associated with the prior art processes is an overall low yield of product buprenorphine. Another drawback associated with the prior art processes is the use of toxic, highly flammable and hazardous solvents in the Grignard reaction step, for example benzene, diethyl ether and THF, making the process unsuitable for scaling-up to industrial scale due to safety and environmental concerns. Additionally, the prior art processes are prone to the formation of by-products/impurities and thus, require extra steps for purification at intermediate stages as well as at the final product stage. This leads to poor yield and inferior quality at intermediate stages as well as at the final product stage. It is clearly mentioned in WO 2013/050748 that when the amino group is substituted with an -alkylcycloalkyl group, such as methyl cyclopropane, the 3-O-demethylation reaction does not work efficiently. The attempted O-demethylation of 3-O-methyl buprenorphine (N-alkylated) gives a conversion to buprenorphine of no more than 2.1% using potassium tert.butoxide and 1-dodecanethiol. The same reaction when attempted using sodium propane thiolate was unsuccessful and no product was detected.
Thus, there remains a need in the art to provide an efficient, industrially scalable process for the conversion of thebaine to buprenorphine and the intermediates thereof, in a high yield and purity.
Further to this, there remains a need in the art to reduce the number of solvents used in the process for preparing buprenorphine and the intermediates thereof, in order to render the process economically viable.